PHARMACOLOGIC AND PHASE I STUDIES OF NEW AGENTS FOR THE TREATMENT OF HUMAN SOLID

新型抗癌药物的开发通常涉及在生化和分子水平上对药物作用机制的广泛研究。在人类中，新分子实体的初始研究传统上将药物药代动力学和药效学测量纳入早期I期研究。然而，由于研究人类受试者明显的技术和后勤困难，细胞内药物效应的测量不太常见。此外，有希望的新药在早期临床试验中未能产生抗癌活性的确切原因往往是未知的。只有设计科学合理的临床试验，将传统的药代动力学终点与细胞内药效学测量相结合，我们才有希望更好地了解新药在人体中的确切作用。这种方法有望阐明为什么在我们的临床试验中研究的新疗法有效或无效。目前，我们的实验室正在将气相色谱、液相色谱和质谱检测等分析技术应用于I期临床研究。这些研究包括使用嘧啶代谢抑制剂（如烯脲嘧啶）对氟化嘧啶进行生化调节的研究。其他正在进行或计划研究的药物包括17-烯丙基氨基-17-去甲氧基格尔达霉素，一种针对头部休克蛋白的新型药物，以及染料木素，一种从大豆中提取的具有癌症预防和生长抑制特性的天然产品。最后，由于在I期研究的患者中使用替代药物的潜在影响，我们正在检查在我们的研究人群中流行的替代药物的流行程度和类型。-结肠直肠癌；

Drug development of new anticancer agent typically involved extensive studies of drug mechanisms of action at the biochemical and molecular level. In humans, initial studies of ne molecular entities traditionally incorporate measurement of drug pharmacokinetics and pharmacodynamics into early phase I studies. However, intracellular measurement of drug effects are less common due to obvious technical and logistical difficulties in study human subjects. Furthermore, the exact reasons why promising new drugs fail to generate anticancer activity in early clinical trials are frequently unknown. Only by designing scientifically sound clinical trials that combine traditional pharmacokinetic endpoint with intracellular pharmacodynamic measurements can we hope to obtain a better understanding of the precise actions of new drugs in humans. This approach will hopefully elucidate why new treatments under study in our clinical trial do or do not work. Currently, our laboratory is applying analytic techniques such as gas and liquid chromotagraphy with mass spectroscopic detection to phase I clinical studies. These include studies of biochemical modulation of fluorinated pyrimidines, using inhibitors of pyrimidine metabolism, such as eniluracil. Other ongoing or planned agents under study include 17-allylamino-17-demethoxygeldanamycin, a novel agent that targets head shock proteins, and genistein, a natural product derived from soy beans with cancer preventative and growth inhibitory properties. Finally, because of the potential impact of the use of alternative medicines in patients enrolled in phase I studies, we are examining the prevalence and types of alternative medicine popular in our study populations. - colorectal cancer,